Cardiac abnormalities in Long COVID 1-year post-SARS-CoV-2 infection

Background Long COVID is associated with multiple symptoms and impairment in multiple organs. Cross-sectional studies have reported cardiac impairment to varying degrees by varying methodologies. Using cardiac MR (CMR), we investigated a 12-month trajectory of abnormalities in Long COVID. Objectives To investigate cardiac abnormalities 1-year post-SARS-CoV-2 infection. Methods 534 individuals with Long COVID underwent CMR (T1/T2 mapping, cardiac mass, volumes, function and strain) and multiorgan MRI at 6 months (IQR 4.3–7.3) since first post-COVID-19 symptoms. 330 were rescanned at 12.6 (IQR 11.4–14.2) months if abnormal baseline findings were reported. Symptoms, questionnaires and blood samples were collected at both time points. CMR abnormalities were defined as ≥1 of low left or right ventricular ejection fraction (LVEF), high left or right ventricular end diastolic volume, low 3D left ventricular global longitudinal strain (GLS), or elevated native T1 in ≥3 cardiac segments. Significant change over time was reported by comparison with 92 healthy controls. Results Technical success of multiorgan and CMR assessment in non-acute settings was 99.1% and 99.6% at baseline, and 98.3% and 98.8% at follow-up. Of individuals with Long COVID, 102/534 (19%) had CMR abnormalities at baseline; 71/102 had complete paired data at 12 months. Of those, 58% presented with ongoing CMR abnormalities at 12 months. High sensitivity cardiac troponin I and B-type natriuretic peptide were not predictive of CMR findings, symptoms or clinical outcomes. At baseline, low LVEF was associated with persistent CMR abnormality, abnormal GLS associated with low quality of life and abnormal T1 in at least three segments was associated with better clinical outcomes at 12 months. Conclusion CMR abnormalities (left entricular or right ventricular dysfunction/dilatation and/or abnormal T1mapping), occurred in one in five individuals with Long COVID at 6 months, persisting in over half of those at 12 months. Cardiac-related blood biomarkers could not identify CMR abnormalities in Long COVID. Trial registration number NCT04369807.


INTRODUCTION
Cardiovascular disease is linked to COVID-19 severity and mortality since the first reports from Wuhan in late 2019. [1][2][3] However, associations between Long COVID symptoms and cardiac impairment are unclear, and the subtypes more likely to recover have not been identified.
In a large post-COVID-19 assessment service in the UK, almost half of individuals where cardiac MR (CMR) scans were performed had evidence of mild myocarditis 4 and in a smaller study, symptom improvement at 6 months was neither correlated with improvement on CMR imaging nor lung parenchymal recovery. 5 A systematic review of CMR findings post-COVID-19 identified myocarditis as the most prevalent diagnosis (14%), 6 though WHAT IS ALREADY KNOWN ON THIS TOPIC ⇒ Acute COVID-19 can be associated with various cardiovascular complications, including myocarditis, ventricular disfunction or acute coronary syndrome, however, the evolution of cardiac impairment, especially in non-hospitalised patients has not been fully investigated.

WHAT THIS STUDY ADDS
⇒ We specify the nature of cardiac abnormalities in Long COVID, linked to clinical characteristics at 1 year. Within a multiorgan context, we provide a holistic view of Long COVID assessment, developed in a community cohort of mainly non-hospitalised individuals with varying severity of symptoms.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
⇒ Comprehensive cardiac MRI assessment may guide clinical decision making and improve healthcare resource utilisation. Evidence of cardiac involvement could inform follow-up assessment and identification of Long COVID subtypes in research and practice, as well as interventional trials to evaluate cost-effective therapies. not all classical features are evident on biopsy, 7 8 and T1 abnormalities and oedema on T2 as the most common findings, and occasional late gadolinium enhancement (LGE). 8 These findings may be present even in absence of elevated cardiac blood biomarkers (eg, troponin or NT-pro-BNP, natriuretic peptide pro B-type natriuretic peptide). 6 9 10 Pericardial effusion and reduced LV and RV function have been occasionally reported, but pericarditis is rare. Nevertheless, to date there is no clear definition of cardiac change post-COVID-19 and cardiac abnormalities in Long COVID at baseline and over time are ill defined in the community setting. Although echocardiography is often the first choice for assessment of cardiac function, CMR is the gold-standard assessment, ensuring a more accurate assessment of cardiac structure and function. We; therefore, conducted a prospective, longitudinal 1-year study using CMR alongside multiorgan MRI assessment, in the largest Long COVID community cohort available to date, to investigate: (1) The evolution of cardiac abnormalities over 1 year after SARS-CoV-2 infection in a multiorgan context; (2) the prevalence and severity of cardiac abnormalities in the non-hospitalised versus the hospitalised population and (3) the associations to patient outcomes that could be used to guide clinical pathway design and identification of at risk individuals.

METHODS Population and study design
The COVERSCAN study (NCT04369807) is a prospective study of organ function using quantitative MRI in individuals recovering from SARS-CoV-2 infection with persistent COVID-19 symptoms in a community setting. Individuals were recruited via advertisement, including in Long COVID support groups and hospital referral (online supplemental methods 1), and invited to undergo CoverScan (Perspectum, Oxford, UK), a multiparametric MRI assessment of lungs, heart, liver, pancreas, kidneys and spleen. All imaging assessments were performed at Perspectum (Oxford), Mayo Clinic (London) and Chenies Mews Imaging Centre (London), between April 2020 and October 2021 (figure 1). Healthy controls were recruited within the same period, Figure 1 Study population for cardiac complications of long COVID. *Individuals were eligible for follow up when MRI abnormality or abnormal bloods in any organ were found at baseline.
Health care delivery, economics and global health care based on self-reporting medical history, and scanned twice on the same date to derive reference ranges and assess repeatability. COVID-19 was classified by either laboratory-confirmed SARS-CoV-2 infection (159 tested SARS-CoV-2-positive by oropharyngeal/nasopharyngeal swab for reverse-transcriptase PCR; 150 individuals with positive antibodies) or strong clinical suspicion of SARS-CoV-2 infection with typical symptoms/signs confirmed by 2 clinicians (245 individuals). Exclusion criteria were symptoms of active respiratory viral infection (temperature >37.8°C or ≥3 episodes of coughing in 24 hours), hospital discharge in the last 7 days and contraindications to MRI, including implanted pacemakers, defibrillators, other metallic implanted devices and claustrophobia. Participants gave written informed consent. Those with organ abnormality at baseline MRI scan (in ≥1 of the following organs: lungs, heart, liver, pancreas, spleen, kidneys) or blood tests were invited back for 6-month follow-up, corresponding to 1-year postinfection. Incidental findings classified as benign and/or not requiring follow-up by an experienced radiologist were not invited for follow-up.

Symptoms, quality of life and function
Presence and severity of symptoms were assessed by selfreport and validated questionnaires: EQ-5D-5L (Euro-QoL-5 dimension-5 level; utility score and quality of life related to usual activities), and Dyspnoea-12 at baseline and follow-up, when Left Ventricular Dysfunction Questionnaire (LVD-36) was also conducted (online supplemental methods 2). For self-reported symptoms at baseline, participants were asked to report only new symptoms arising since the COVID infection; at follow-up, they were asked to report symptoms since baseline. Time off work due to Long COVID was recorded as total number of days at follow-up.

Blood investigations
Two blood samples were taken at both timepoints, on the same day as the MRI scan: one immediately sent for analysis, the other fractionated and frozen for later analysis (online supplemental methods 3).

Multiorgan imaging
Participants were scanned at Perspectum Gemini (Oxford: n=338; MAGNETOM Aera 1.5T scanner) and Mayo Clinic (London: n=198; MAGNETOM Vida 3T) (both scanners: Siemens Healthcare, Erlangen, Germany), at baseline and follow-up with multiorgan, multiparametric MRI assessment (total ~40 min duration). All imaging methods were deployed in standard clinical MRI scanners using slightly modified versions of previously published methods 11 12 and using short (<14 s) breath-holds except for lung imaging (online supplemental methods 4 and 5).
After each visit, participants and if requested their primary care physicians also, received a clinical summary and a report informing on the MRI data, where quantitative metrics were referenced against the healthy control population, and one on the blood biomarker data.

Reference ranges and repeatability coefficients
In parallel, 92 sex-matched and age-matched healthy individuals (online supplemental methods 6 tables S1,S2) were recruited and scanned twice on the same day, to derive a control group. Reference ranges using the healthy control population were calculated for each metric by computing 2.5% and 97.5% percentiles using bootstrapping (100 000 permutations), except pancreas proton-density fat fraction (PDFF), where the 95% percentile was for the upper limit, and liver cT1 and PDFF, where we used established thresholds. 13 Reference ranges for organ length and volume required larger sample size for sex and height stratification, so we used a sample of 1836 individuals from UK Biobank without selfreported diabetes or hypertension. To evaluate measurement repeatability, two separate scans were performed in healthy controls (1.5T, n=59; 3T, n=33) on the same day. After first scan, the participant had a 10 min break out of the scanner before a second identical scan. Technical success was assessed by quality-assured measures for each variable, and overall, in report delivery for each patient (online supplemental table S1).
Definition of cardiac and multiorgan abnormality CMR abnormalities were defined by consensus among expert cardiologists with experience of Long COVID patients and following literature review of common cardiac findings post-COVID-19 as: ≥1 of the following outside reference range left or right ventricular ejection fraction (LVEF or RVEF) or left or right ventricular end diastolic volume, global longitudinal strain (GLS) (abnormal will be referred as low, in absolute values) or ≥3 quantitative T1 mapping segments. Two cardiologists independently reviewed all CMR findings ahead of statistical analysis in this work. Multiorgan impairment was defined as ≥2 measurements outside reference ranges in a further organ (excluding elevated liver or kidney volume) 11 (further details in online supplemental methods 5 table S1).

Statistical analysis
We used R software V.4.0.4 and p values <0.05 defined statistical significance. Normality was assessed using Shapiro test. To describe parametric and non-parametric variables, we used mean (SD) and median (IQR), respectively. For categorical variables, we reported frequencies (percentage). For groupwise comparisons of continuous parametric and non-parametric, and categorical variables, t-test, Wilcoxon rank sum and Fisher's exact tests, respectively, were used, without correction for multiple testing as analyses were exploratory. Baseline and follow-up metrics were assessed using reference ranges calculated in healthy controls. Repeatability coefficients (RC) for each CMR metric in healthy controls determined the smallest detectable difference between repeated measures. 14 For cases with CMR abnormalities at baseline, findings were considered: (A) ongoing when CMR metrics were outside reference ranges at follow-up, independently from RC, (B) resolved when change was >RC and CMR metrics were within reference ranges at follow-up. In cases without baseline CMR abnormalities, participants were considered: (A) never affected when CMR was within reference ranges at follow-up, independently from RC, (B) with new onset findings when change was >RC and CMR metrics were outside reference ranges at follow-up. Associations with all exposures were by logistic and linear regression for categoric and continuous dependent variables, respectively. Variables with a significance >0.05 in the univariable models were included in the multivariable analyses. Goodness of fit was performed comparing the actual versus predicted values for an outside validation cohort and doing a visual inspection of residuals of the model. Multivariable stepwise regressions were performed to assess which cardiac metrics at baseline, as continuous variables, were most predictive of poor quality of life, reduced symptom severity and ongoing CMR findings between baseline and follow-up to inform future clinical care.
Community-delivered diagnostic assessment Technical success of CMR was determined by reporting quality-assured measures for each variable reported here, and of multiorgan MRI overall, in delivering a report for each patient. For cardiac T1 and T2, technical success was based on value availability for least three AHA segments. Clinical utility of MRI metrics was not directly assessed during the study, as they were used for research only.
In exploratory analyses, no blood investigations were predictive of CMR abnormalities at 6 months and a full table with prevalence of blood abnormalities and group can be found in online supplemental table S4. At 6 months, 62/102 (62%) individuals with CMR abnormalities presented with severe Long COVID, based on questionnaires (Supplementary methods). Forty-three (43%) and 44 (44%) individuals had severe and moderate symptoms, respectively; most commonly fatigue (100%), shortness of breath (88%), headache (83%), chest pain (81%) and cough (80%). Symptom prevalence was similar regardless of the CMR abnormalities category (table 1).
Follow-up CMR data were available in 330/331 individuals at a median 12.7 (IQR: 11.6-14.3) months since first symptoms; these individuals were all symptomatic at baseline. At 12 months, 51/330 (15%) presented with CMR abnormalities. Of the 102 individuals with CMR abnormalities at 6 months, 71 had follow-up data available (figure 1).

Resolved CMR abnormalities
At 12 months CMR abnormalities had resolved in 30/71 (42%). At 6 months, CMR in this group showed elevation in T1 (57%), low GLS (21%) and reduced LVEF (20%), with full resolution by 1 year (table 2). By 12 months, 53% had fully resolved multiorgan impairment, and only 1 individual had impairment in ≥3 organs (table 3). Alongside resolution of CMR findings, elevation of NT-proBNP observed at baseline in a single patient of 41 years had resolved by 12 months. No blood investigations were predictive of cardiac recovery (online supplemental table  S4).
Symptoms and impact on usual activities as well as quality of life were similar between the ongoing and resolved CMR abnormalities groups. Of 41, 16 (39%) individuals with ongoing CMR abnormalities still presented with severe Long COVID; however, most of Health care delivery, economics and global health care    2).

Multiorgan MRI (including CMR) and integrated clinical assessment
Technical success of multiorgan MRI was 99.1% and 98.3% at baseline and follow-up assessments, respectively. Technical success of CMR and integrated in-person assessment was 99.6% at first visit and 98.8% at follow-up.

DISCUSSION
In the largest community-based study to-date with cardiac MR follow-up over 1 year in a mainly non-hospitalised, post-COVID-19 cohort with little prior cardiac disease, we report three new findings. First, CMR abnormalities were common (one in five individuals at 6 months) and commonly persisted (three out of five individuals at 12 months). Second, CMR abnormalities were found even without acute COVID hospitalisation (83/462, 18%). Third, cardiac blood biomarkers and symptoms were not predictive of composite CMR abnormalities but abnormal individual CMR parameters (eg, LVEF, 3D global longitudinal strain and cardiac T1) were associated with ongoing CMR findings, lower quality of life or reduced symptom severity at 12 months.

Characteristics and trajectory of cardiac abnormalities
Our results indicate that, despite women being more affected by Long COVID, men have higher risk of cardiac abnormalities. 15 Potential contributory factors include: influence of biological sex on expression and regulation of ACE 2, sex differences in genetic and hormonal   Health care delivery, economics and global health care  Health care delivery, economics and global health care regulation of immune responses, 16 sex-dependent patterns of coagulation, smoking or drinking. 4 5 17 18 Published CMR studies in Long COVID vary by study design, cohort, follow-up duration, definition of cardiac abnormalities and estimated prevalence of cardiac abnormalities (26%-60%). 6 11 19-23 A recent review 9 highlighted under-representation of affected individuals from community-based settings, especially monitoring nonhospitalised individuals over time, which we address in this study. When COVID-19-related and classical myocardial injury are compared, 8 only 9% of individuals fulfil acute myocarditis criteria and those with more severe disease are more likely to exhibit chronic inflammation and impaired cardiac function. We report prevalence of CMR abnormalities (19% and 15% at 6 and 12 months) consistent with previous studies, providing standardisation of metrics and definition, which can be used at scale in research and practice to document and monitor cardiac abnormalities. 6 11 16 19 20 We confirm that abnormalities in T1 (in line with previous research, 6 9-11 19 22 T2 and LGE, as well as functional abnormalities, 5 11 23 24 are most common in Long COVID patients. Acute COVID can present with myocardial inflammation; ongoing COVID-19 patients can also have myocarditis, but it is harder to diagnose, and often missed with echocardiography. More pertinently, the observed functional changes may be due to inflammation and other aetiologies (eg, pulmonary disease, microinfarctions, metabolic dysregulation), and further mechanistic work is required to explore associations with CMR markers seen here.

Impact of acute hospitalisation for COVID-19 on cardiac abnormalities
Most individuals presenting with CMR abnormalities at baseline did not require acute COVID-19 hospitalisation (81%). One individual with elevated cardiac-related blood biomarkers had CMR abnormalities at 6 months and acute COVID-19 hospitalisation. Blood biomarkers and symptoms did not differentiate hospitalised and non-hospitalised groups. On MRI, cardiac T1 abnormalities 4 25 and multiorgan involvement (particularly renal) 5 11 19 were more prevalent in those with CMR abnormalities and acute COVID-19 hospitalisation, as in other published studies. 8 13 26 27 Clinical management pathways in Long COVID populations at risk of cardiac abnormalities Cardiac-related blood biomarkers may be raised in early convalescence from COVID-19, 28 but did not aid detection of CMR abnormalities in Long COVID in our study, despite 19% having CMR abnormalities, supported by other research. 5 23 24 Burden and improvement in symptoms 6 months after COVID-19 were neither correlated with resolution on CMR nor lung parenchymal recovery. 5 Early MRI assessment may identify organ-specific impairment (including cardiac), leading to early referral for appropriate specialist assessment and treatment, in contrast to the experience of many patients who are currently having multiple appointments with multiple specialists for multiple assessments. In a cluster-randomised design, the STIMULATE-ICP trial is currently evaluating whether multiorgan MRI (Coverscan) can aid diagnosis and follow-up of cardiac and multiorgan impairment in Long COVID, and reduce burden to healthcare systems, already struggling due to COVID-19-related lack of resources and backlogs, while achieving integrated care. 29 Cardiac findings could inform design of Long COVID treatment algorithms. Abnormal GLS is associated with cardiac remodelling (indicative of more severe cardiac disease), 26 and predictive of low quality of life at 12 months. Elevated T1 was predictive of lower symptom severity at 12 months. There may be multiple cardiac subgroups in Long COVID, potentially detected by CMR early postinfection. These subtypes may be related to pulmonary hypertension, 13 pre-existing comorbidities 27 and post-COVID-19 myocardial inflammation, 8 but require further study and validation.
Comprehensive multiorgan MRI assessment may help clinical decision making and improve healthcare access and provision. Evidence of cardiac involvement could guide follow-up assessment and identification of Long COVID subtypes in research and practice. Interventional trials with prespecified subgroup analysis and improved definitions of cardiac abnormality (not only myocarditis centred), are required to inform cost-effective therapies.

Strengths and limitations
This is the largest longitudinal study to-date of cardiac abnormality in Long COVID with detailed biochemical and imaging characterisation of multiorgan function starting in April 2020. We included healthy, age-matched controls. All MRI was non-contrast. We recruited a realworld cohort at lower risk of COVID-19 severity and mortality. Unlike other studies, 30 our approach offers quick, scalable assessment using standard MRI scanners. There are limitations. First, our CMR protocol excluded gadolinium contrast, the main reason for this was to reduce the scanning times, contact-time between the patient and the healthcare worker, and to avoid potential renal complications related to COVID-19. This was backed by previous research, supporting the use of native non-invasive T1 mapping to characterise myocardial inflammation, 26 and did not have sufficient statistical power in cardiac T2 collection, relying on native noninvasive T1 mapping to characterise myocardial inflammation, validated for acute myocarditis. 31 Second, we are not able to define whether these individuals presented with multiorgan abnormalities before their COVID-19 infection, although clinical diagnoses were recorded. Third, we did not have follow-up scans on individuals without impairment at baseline and a third of patients with CMR abnormalities at baseline withdrew or were lost to follow-up. Fourth, we did not have pre-COVID-19 cardiac or multiorgan imaging available in participants. Fifth, our study population was not ethnically diverse, and COVID-19 has disproportionately affected non-white individuals. In addition, our study recruited patients during the first wave of the pandemic, when testing was not broadly available, mainly via patient support groups rather than a systematic screen of post-COVID-19 patients, as Long COVID clinics were only set up at the end of our recruitment and this may represent a bias.

CONCLUSION
CMR shows that cardiac abnormality persists in Long COVID in some individuals up to 12 months after first symptoms. CMR abnormalities (left ventricular or right ventricular dysfunction/dilatation and/or abnormal T1mapping), are associated with acute COVID-19 hospitalisation and male gender, but subtypes of disease (based on symptoms, examination and investigations) are yet to be established. Therapeutic options and effective clinical pathways require urgent clinical trials.